Project Summary & Abstract The timing of energy intake relative to the light-dark and sleep-wake cycle plays an important role in the development of metabolic diseases. Consuming energy at an inappropriate time of day results in desynchrony of anabolic and catabolic processes that are regulated across the day by circadian clock systems. When mice are fed a high fat diet ad libitum, they eat throughout day and night and become obese, but strikingly when the same diet is restricted to a short window at the appropriate circadian time (i.e., time time-restricted feeding; TRF), they are protected against obesity. Little is known in humans regarding the influence of meal timing on whole body metabolism and the mechanisms involved. The overarching research goal of the present K01 Career Development Award is to leverage the pre-clinical evidence on the TRF paradigm in mice to understand how meal timing affects fuel metabolism, metabolic flexibility, and organization of the circadian landscape in humans. The proposed research plan serves as a vehicle to advance the applicant, Corey Rynders, PhD to independent investigator status over a period of five years of NIH-NIDDK K01 support. Dr. Wendy Kohrt at the University of Colorado ? Anschutz Medical Campus and a multidisciplinary group of scientists with expertise in obesity, metabolism, and circadian physiology (Drs. Bessesen, Melanson, and Wright) will oversee the training plan of Dr. Rynders and ensure his successful transition to an independent translational researcher. To achieve this aim, Dr. Rynders will need to gain new knowledge of circadian physiology, establish important collaborations in the circadian field, mature his expertise in metabolic research, and have protected time to acquire preliminary data to submit a competitive R01 application. The overall career goal is to develop an independent research program focused on how lifestyle factors impact the circadian regulation of metabolism in human subjects. Study Design: The study will determine the effects of time-of-day-dependent feeding on substrate metabolism, metabolic flexibility, and circadian clock gene expression. Overweight adults (n=28) will complete two isocaloric feeding conditions using a randomized cross-over design; 7 days free-living with day 8 spent in a room calorimeter to measure substrate oxidation. Subjects will complete a simulated ad libitum feeding condition with fasting duration equal to sleep duration and an isocaloric TRF condition with energy intake restricted to an 8h window during the early or late or late part of wakefulness (half of the subjects will be randomized to early TRF and the other to late TRF; n=14 per group). Aim 1 will test whether TRF increases dietary fat oxidation, 24h whole body fat oxidation, and the metabolic flexibility to fasting. Aim 2 will determine whether TRF decreases 24h glucose and insulin concentrations, increases insulin sensitivity, and improves the metabolic flexibility to feeding. Finally, Aim 3 will obtain fundamental data on how meal timing influences the organization and activity of the central clock (melatonin rhythm) and peripheral clocks (clock gene rhythms measured in blood). Relevance: Meal timing is a modifiable behavior and may be a strategy against obesity and metabolic disease.